The recent advances in the understanding of the determinants of cellular entry by HIV (e.g., chemokine receptors as coreceptors and key factors in strain-specific tropism) provide a crucial platform upon which transgenic animal models of human HIV disease could be constructed for the investigation of interactions between HIV and the host that underlie development of vaccines and other treatments. Accumulating evidence indicates that dominant post-entry restrictions to viral replication in mice are likely to restrict markedly the use of genetically modified mice for this purpose in the near-term. Other animals such as rabbits have been used in limited transgenesis efforts for various research purposes in the past, and represent a potential alternative for studies of HIV disease. The applicants have recently developed evidence based on gene transfer in cell culture systems that rabbit cells are significantly more permissive for these post-entry steps in the replication of HIV-1 than are murine cells. This proposal therefore seeks to pursue the development of transgenic rabbits as a novel small animal model of HIV disease. These animals will carry transgenes encoding human CCR5 and/or CXCR4, both of which have been implicated strongly as critical determinants of the pathogenesis of AIDS. In addition, these animals will carry genes encoding the human CD4 molecule, which remains an important receptor for many strains of HIV.